Replication Study Research Articles

Linked Data for modelling and replicating the knowledge production process in data-driven humanities research

Abstract The steps from primary source to scholarly claim typically follow a ‘breadcrumb trail’ of wide-ranging decisions by one or more scholars. For replication studies, these decisions must be identified and made as explicit as possible so that the results can be faithfully reproduced. We use a replication study of premodern population estimates as a use case to gain more insight into the kinds of scholarly practices that need to be made explicit, and to think about possible solutions for modelling this process with future replicability in mind. We argue that Linked Data is the logical and flexible technique for modelling such a replication study. For our use case, it allows us to capture both the data itself and the individual decisions made to arrive at a scientifically derived population estimate based on, for example, geographical phenomena or source criticism. In this article, we set an agenda for the use of Linked Data in data-driven humanities research by exploring the benefits, opportunities, and challenges associated with using Linked Data to conduct a replication study in the humanities (and to promote the reproducibility of humanities research more generally). We identify three key aspects that can benefit from the flexibility offered by Linked Data: increasing the trustworthiness of quantitative studies; facilitating the reproducibility of future studies; and facilitating the interpretation of replication results.

A Simple Strategy for Identifying Conserved Features across Non-independent Omics Studies.

False discovery is an ever-present concern in omics research, especially for burgeoning technologies with unvetted specificity of their biomolecular measurements, as such unknowns obscure the ability to characterize biologically informative features from studies performed with any single platform. Accordingly, performing replication studies of the same samples using different omics platforms is a viable strategy for identifying high-confidence molecular associations that are conserved across studies. However, an important caveat of replication studies that include the same samples is that they are inherently non-independent, leading to overestimating conservation if studies are treated otherwise. Strategies for accounting for such inter-study dependencies have been proposed for meta-analysis methods devised to increase statistical power to detect molecular associations in one or more studies. Still, they are not immediately suited for identifying conserved molecular associations across multiple studies. Here, we present a unifying strategy for performing inter-study conservation analysis as an alternative to meta-analysis strategies for aggregating summary statistical results of shared features across complementary studies while accounting for inter-study dependency. This method, which we call "adjusted maximum p-value" (AdjMaxP), is easy to implement with inter-study dependency and conservation estimated directly from the p-values from each study's molecular feature-level association testing results. Through simulation-based assessment, we demonstrate AdjMaxP's improved performance for accurately identifying conserved features over a related meta-analysis strategy for non-independent studies. AdjMaxP offers an easily implementable strategy for improving the precision of analyses for biomarker discovery from cross-platform omics study designs, thereby facilitating the adoption of such protocols for robust inference from emerging omics technologies.

Moderation of thyroid hormones for the relationship between amyloid and tau pathology

BackgroundAltered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aβ) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aβ and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aβ and tau deposition.MethodsThis cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET.ResultsNo associations were found between either thyroid hormones or TSH and Aβ and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aβ on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aβ deposition was not significant, whereas the interaction between fT3 and Aβ deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aβ and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aβ on tau deposition.ConclusionOur findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aβ and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aβ-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.

Longitudinal investigation of early mathematical achievement and classroom strategic diversity: A replication and extension study

Developing solution strategies, effortful procedures that students employ to solve a specific problem, is an important mathematical goal. Studies have documented intraindividual strategy variability and its significance for learning, but only some have addressed the interindividual strategic diversity across students within a classroom. This study analyzed classroom strategy diversity using assessments of 527 kindergartens to 2nd-grade students. Latent growth modeling analysis revealed that the best fit was a spline model featuring two phases of linear growth with different growth rates (i.e., one in Kindergarten, the other from Kindergarten spring to second grade). A growth mixture modeling analysis demonstrated that only one latent class existed within the data, which supports the homogeneity of the identified growth trajectory among students. We also analyzed the relations of their learning to the interindividual strategy diversity in their classrooms via a multilevel latent growth model. The results showed that early encouragement of student-generated strategies and later guidance toward research-based effective strategies most supported mathematical growth. This finding aligned with the previous work regarding classroom strategic diversity. Educational relevance and implications statementDeveloping solution strategies is an important mathematical goal. Do children benefit from being in classrooms using diverse strategies or a smaller range of efficient strategies? Does this depend on children's phase of learning? We found that early encouragement of student-generated strategies followed by later guidance toward research-based effective strategies most supported mathematical growth.

Communal-brand connection and service loyalty: the mediation effect of corporate reputation and customer satisfaction among retail banking customers

PurposeThe study explores the dynamics among communal-brand connections, corporate reputation, customer satisfaction and their collective influence on service loyalty within the retail customer segment of commercial banks.Design/methodology/approachHypotheses are proposed for a parallel and serial-mediated model, in which corporate reputation and customer satisfaction mediate the influence of communal-brand connections on service loyalty. Data are collected from a sample of retail customers of commercial banks in a European country.FindingsFindings indicate that individuals who perceive a strong affiliation with a brand that emphasises community engagement are more likely to demonstrate loyalty to that brand. Results highlight the need for managers allocate resources to cultivate community initiatives that foster communal-brand connection in their drive to improve service loyalty.Research limitations/implicationsA non-representative sample was collected, with a focus on a limited set of variables and employing a unidimensional measure of service loyalty. Additionally, the significance of communal-brand connection may vary across brands, warranting replication studies among smaller banks.Practical implicationsRecognition of communal-brand connection as an important driver of customer loyalty suggests that customers are motivated by intrinsic positioning factors related to the community. As part of their positioning, commercial banks can leverage their marketing and communication efforts to foster community development, thereby enhancing customer identification, connection and narratives that foster belongingness among customers.Originality/valueThe model of direct and mediated model of communal-brand connection on service loyalty has not been previously explored. Moreover, the research is conducted among retail bank customers that representing a context seldom considered in the domain of brand communities.

Prior Context and Individual Alpha Frequency Influence Predictive Processing during Language Comprehension.

The extent to which the brain predicts upcoming information during language processing remains controversial. To shed light on this debate, the present study reanalyzed Nieuwland and colleagues' (2018) [Nieuwland, M. S., Politzer-Ahles, S., Heyselaar, E., Segaert, K., Darley, E., Kazanina, N., et al. Large-scale replication study reveals a limit on probabilistic prediction in language comprehension. eLife, 7, e33468, 2018] replication of DeLong and colleagues (2015) [DeLong, K. A., Urbach, T. P., & Kutas, M. Probabilistic word pre-activation during language comprehension inferred from electrical brain activity. Nature Neuroscience, 8, 1117-1121, 2005]. Participants (n = 356) viewed sentences containing articles and nouns of varying predictability, while their EEG was recorded. We measured ERPs preceding the critical words (namely, the semantic prediction potential), in conjunction with postword N400 patterns and individual neural metrics. ERP activity was compared with two measures of word predictability: cloze probability and lexical surprisal. In contrast to prior literature, semantic prediction potential amplitudes did not increase as cloze probability increased, suggesting that the component may not reflect prediction during natural language processing. Initial N400 results at the article provided evidence against phonological prediction in language, in line with Nieuwland and colleagues' findings. Strikingly, however, when the surprisal of the prior words in the sentence was included in the analysis, increases in article surprisal were associated with increased N400 amplitudes, consistent with prediction accounts. This relationship between surprisal and N400 amplitude was not observed when the surprisal of the two prior words was low, suggesting that expectation violations at the article may be overlooked under highly predictable conditions. Individual alpha frequency also modulated the relationship between article surprisal and the N400, emphasizing the importance of individual neural factors for prediction. The present study extends upon existing neurocognitive models of language and prediction more generally, by illuminating the flexible and subject-specific nature of predictive processing.

A replication study using the World Health Organization pharmacovigilance database (VigiBase®) to evaluate whether an association between ketamine and esketamine and alcohol and substance misuse exists

Background and objectivesKetamine and esketamine are increasingly prescribed in the treatment of resistant mood disorders and persons at risk of suicide. Ketamine is a drug of misuse with increasing non-therapeutic use in the general population. Herein, our aim was to determine whether ketamine and/or esketamine are disproportionately associated with reports of substance and/or alcohol misuse. MethodsReplicating a similar analysis recently conducted using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, we identified cases of “alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder (SUD), substance abuse, drug dependence, drug use disorder and drug abuse” in association with ketamine and esketamine reported to the World Health Organization Pharmacovigilance Database (WHO VigiBase). We searched the database from inception to January 2024. The reporting odds ratio (ROR) of each of the aforementioned parameters was calculated; acetaminophen was used as the control. The numerator of the equation represents the number of cases (n) and the denominator represents the total cases of psychiatric disorders (N). Significance was obtained when the lower limit of the 95 % confidence (CI) > 1.0. ResultsThe RORs for ketamine was increased for most parameters (i.e., alcohol abuse (3.24), substance dependence (12.48), substance use disorder (170.44), substance abuse (2.94), drug dependence (2.88), drug use disorder (11.54) and drug abuse (2.85), respectively). With respect to esketamine, the RORs were observed to be different from ketamine insofar as we observed a reduction in the RORs for three parameters (i.e., substance abuse (0.41), drug dependence (0.083) and drug abuse (0.052), respectively). The IC025 values were significant for ketamine in cases of alcohol abuse (0.35), substance dependence (0.50), substance use disorder (2.77), substance abuse (0.83), drug dependence (0.97), drug use disorder (1.95) and drug abuse (0.94). Additionally, oxycontin showed significant IC025 values for substance use disorder (0.0014), substance abuse (0.042), and drug dependence (0.17). ConclusionEsketamine was not associated with an increased ROR for any parameter of alcohol and/or substance use disorder. Mixed results were observed with ketamine with some RORs increased and others decreased. Estimating RORs using a pharmacovigilance database does not establish causation in the case of elevated RORs and cannot be assumed to be a therapeutic effect when lower RORs were observed.

TEACHERS INTERPERSONAL BEHAVIOR AND PARENTAL ENGAGEMENT IN RELATION TO THE STUDENT’S ACADEMIC PERFORMANCE

The primary purpose of this study is to determine whether teachers’ interpersonal behavior and parental engagement in relation to the students' academic performance. This study employed a descriptive-correlational research design. Using total population sampling, 315 junior high school students were selected as respondents from one of the junior high school in New Bataan during the school year 2023-2024. Furthermore, this study employed two adapted survey questionnaires and the general average of the students during their third quarter; all validated to collect data and treated using mean, standard deviation, and Pearson-r. The findings showed that teachers’ interpersonal behavior and parental engagement among the students are very high, while their academic performance are very satisfactory. The results also revealed that teachers’ interpersonal behavior positively correlated with students’ academic performance and parental engagement negatively correlated with students’ academic performance. These results encourage teachers and parents to continue support and have a good relationship with the children to maintain a good academic performance of students. Furthermore, to improve the applicability of the results, it is imperative to carry out replication studies in various locales. This will validate the durability of these relationships beyond the present research setting and contribute to a more comprehensive comprehension of these issues. KEYWORDS: Teachers’ interpersonal behavior, parental engagement, student academic performance, junior high school students, descriptive-correlational design, pearson correlation coefficient, Davao de Oro, Philippines.

The Impact of Reading on Children’s Cognitive and Language Development

Literature has always been regarded as one of the best methods available that can positively influence the development of young preschool and kindergarten children, but also older school kids. However, in order for it to make a significant impact, we need to make sure that the content that is being read is appropriate for the age of the children we are reading to. If young children are exposed to adult literature or such that they cannot understand at their language level, it does not help their language improvement and development. In order for literature to make a full impact on both language and cognitive development, we need to use appropriate materials to reach satisfying results, in this case, genres which have been specifically crafted for the language level of the targeted audience. The aim of this paper was to explore the impact of reading to children (specifically literature designed for their language level) by doing a replication study based on the paper done by Fekonja et al. (2007), analyse the results and compare the two classes on a language measurement scale in order to see the impact of literature on language development. The results showed a significant difference in language development between the two groups, favouring the experimental group, which reinforces the importance of incorporating systematic reading of children’s literature into educational practices.

Positive correlation between working memory and face-to-face social interaction in everyday life

Working memory (WM) plays a crucial role in various cognitive tasks from language comprehension to problem-solving. However, its influence on social activities has remained largely unexplored. The current two studies on individual differences, a pilot (N = 329) and a pre-registered direct replication (N = 338) study, investigated the relationship between WM and outside-the-lab social interaction by using a listening span task and three social network questionnaires (e.g., how many people a participant had contacted in the past month). The consistent patterns in the two studies were (a) WM recall was positively correlated with social network size, (b) WM recall remained positively correlated with social network size even when accounting for online interactions on WhatsApp and Facebook, and (c) WM recall was positively correlated with social network size by face-to-face interaction. These novel findings would suggest connections between WM and face-to-face social interaction. It was, however, acknowledged that the obtained effect sizes were small, and that further investigation is indeed necessary. In light of this, we also clarify future directions for understanding the relationship between WM and social interaction.

Swedish teacher conceptions of assessment: a focus on improving outcomes

ABSTRACT Understanding teachers’ conceptions of assessment is a key objective in supporting assessment practices that lead to improved learning outcomes. Thus, inventories capable of identifying teachers’ assessment conceptions are important. The Teachers Conceptions of Assessment (TCoA) inventory was an early and influential measure of teacher assessment conceptions, but replication studies have shown that the model may be affected by policy and practice context. In the present study, a Swedish adaptation of the TCoA was administered twice, 18 months apart. A sample of 249 teachers were matched across the 2 time-points and their self-reported scores were analysed with confirmatory factor analysis and invariance testing. With good correspondence to the data, six of the nine factors in the TCoA were completely replicated and one factor was partially replicated. The model had sufficient similarity between time points to permit mean score comparisons, which were largely equivalent between times. The study indicates that the Swedish Teacher Conceptions of Assessment adaptation can be used reliably in Swedish primary and lower secondary schools as measure of teacher conceptions of the uses of assessment.

Evaluation of the associations of interlukin-7 genetic variants with toxicity and efficacy of immune checkpoint inhibitors: A replication study of a Japanese population, based on the findings of a European genome-wide association study.

Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population. From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders. In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p=0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p=0.015) in the univariate analysis and 0.315 (p=0.023) in the multivariate analysis. In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. UMIN Clinical Trials Registry with the number UMIN000043798.

Accent Bias in Professional Evaluations: A Conceptual Replication Study in Brazil

Abstract Evidence from Canada suggests that accent bias can be moderated by speakers’ demonstrated job-relevant performance and the prestige level of their occupation (Teló et al. 2022). In this study, we replicated Teló et al.’s (2022) work in Brazil. First language (L1) Brazilian Portuguese-speaking listeners rated audio recordings of L1 Brazilian Portuguese and L1 Spanish speakers along continua capturing one professional (competence), one experiential (treatment preference), and one linguistic (comprehensibility) dimension. Our findings challenge the notion of consistent bias, as listeners did not uniformly perceive L1 Brazilian Portuguese speakers as more competent and comprehensible than L1 Spanish speakers, and, in fact, generally preferred treatment provided by L1 Spanish speakers. Complex interactions provided a nuanced account of listeners’ evaluations, revealing, among other patterns, that demonstrated performance level and job prestige affected the evaluated dimensions differently depending on the speaker’s L1. This replication further expands the initial study by examining the role of four listener variables as predictors of speaker ratings. Greater listener familiarity with the context depicted in the script was associated with the assignment of higher ratings overall.

Artificial Intelligence or Nursing Student? Revisiting Clues in the Connectives.

Recent research at a single-purpose nursing institution has suggested a means to authenticate student writing by distinguishing it from artificial intelligence (AI)-generated text through the detection of key terms. The purpose was to replicate and expand the research that identified key terms present in student writing but absent from AI-generated text. A total of 5 generative AI writing tools were fed prompts to collect 14 787 words. Using the Search function on word processing software, the frequency of the terms, because, since, so, then, thing, think, and too, was measured and compared against earlier published findings from AI and students. The replication study was successful for the terms since, then, thing, think, and too. Measuring key term frequency may be a path to authenticate student writing. While no tool can provide certainty of original authorship, the absence of key terms in a student submission may suggest AI authorship.

P-756 Neurodevelopmental outcomes at school-age after conception with hysterosalpingography using iodinated contrast media - follow-up of the nationwide multicentre H2Oil trial

Abstract Study question How does conception <6 months after hysterosalpingography (HSG) with iodinated contrast media affect the neurodevelopment of the offspring compared to naturally-conceived peers at a school-age? Summary answer Children conceived <6 months after HSG with iodinated contrast media perform lower on intelligence tests and information processing and attention control compared to naturally-conceived peers. What is known already Tubal patency in subfertile women is commonly assessed using hysterosalpingography (HSG), but the potential risks of exposure to high iodine content in contrast media used remains unknown. Exposure to iodine excess can cause transient reduction in thyroid hormone synthesis due to the Wolff-Chaikoff effect. Thyroid hormone sufficiency in early pregnancy is vital for children’s neurodevelopment. When conception occurs shortly after HSG with iodinated contrast, a temporary reduction of maternal and/or foetal thyroid hormone supply could jeopardize children’s neurodevelopment. Study design, size, duration We evaluated neurodevelopmental outcomes of 6–9-year-old children conceived <6 months after HSG with oil-based (iodine content: 480mg/ml) or water-based contrast (iodine content: 240-300mg/ml) in a nationwide randomised controlled trial (H2Oil trial; Netherlands; 2012-2014; NCT05168228). Naturally-conceived children (n = 44) with similar age, sex and parental education were used as a comparison group (NTR9574). We also compared children conceived <4w, 4-12w, >12w after HSG with those conceived naturally. The study took place January 2022 until November 2023. Participants/materials, setting, methods We contacted 140 mothers from the H2Oil trial, 69 children conceived <6m after HSG participated, and parallelly we recruited 44 naturally-conceived children. Primary outcomes were intelligence (Wechsler’s Intelligence Scale for Children V), behavioural functioning (SDQ and SWAN, administered to parents and teachers), and academic performance. Secondary outcomes were neurocognitive function assessed by a battery of computerized tests. We used linear regression adjusted for age, sex, and parental education and applied FDR correction. Main results and the role of chance Compared to naturally conceived children, children conceived <6m after HSG had lower performance on intelligence tests (-6.81; 95%CI-10.97 to -2.65; p = 0.02) and the neurocognitive domain Processing & Control (-0.52; 95%CI-0.84 to -0.19; p = 0.02), with functions relating to information processing speed and consistency affected. No differences were found for other neurocognitive domains, behaviour or academic performance. Considering time between HSG and conception, intelligence scores were lower for children conceived <4w after HSG compared to naturally-conceived peers (-11.47; 95%CI-17.98 to -4.95; p = 0.03), while no significant differences were found for the groups of children conceived 4-12 weeks after HSG (-7.17; 95%CI -12.28 to -2.06; p = 0.10) or > 12 weeks after HSG (-4.20; 95%CI -9.33 to 0.94; p = 0.52). The findings of this study warrant replication in larger independent samples in order to evaluate the long-term neurodevelopment of children conceived after HSG with iodinated contrast media. Limitations, reasons for caution We aimed to recruit 64 children for each group, but our study was not sufficiently powered for small- and medium-sized differences. We did not collect information on the thyroid or iodine status of the mothers following HSG, and there is limited knowledge about pharmacokinetics of iodinated contrast media in humans. Wider implications of the findings Replication studies with are needed to further evaluate the safety of iodinated contrast media use periconception, including their effects on thyroid function and children’s neurodevelopment. Closer monitoring and treatment of thyroid dysfunction in the months following HSG may be warranted. Trial registration number NCT05168228

Effects of Cannabis Use on Sedation Requirements for Endoscopic Procedures: A Replication Study.

On July 1, 2021, cannabis became legal in Virginia for adults 21years of age and older. Cannabis consumption may have significant implications for outcomes related to medical care, including procedural sedation. The purpose of this study was to determine whether self-reported cannabis consumption has any relationship to sedation medication requirements during endoscopic procedures. A retrospective analysis was conducted to examine two groups of surgical patients (self-reported cannabis use versus self-reported non-cannabis use) at a community hospital in the mid-Atlantic region. Results demonstrate that there were no significant differences between groups for either Time to Aldrete ≥8 (p =.486) or Time to Meet Phase II Criteria (p =.762). Equivalent recovery times for both groups may be an indicator that comparable sedation levels were maintained, despite the increased propofol requirements of the cannabis group. Open conversations to establish patient use of cannabis products prior to procedural sedation is important for determining appropriate plans of care related to risk factors and medication dosage requirements during endoscopic evaluations.

A framework for evaluating reproducibility and replicability in economics

AbstractWe propose a framework for evaluating reproducibility and replicability in economics. Reproducibility is defined as testing if the results of an original study can be reproduced using the same data and replicability is defined as testing if the results of an original study hold in new data. We further divide reproducibility and replicability studies into five types: computational reproducibility, recreate reproducibility, robustness reproducibility, direct replicability and conceptual replicability. In addition to this typology we propose indicators to measure the degree of reproducibility and replicability in both individual studies and for a group of studies.

Understanding researchers' perceptions and experiences in finance research replication studies: A pre-registered report

A fundamental principle of responsible scientific research is replication. Replication provides independent verification of previously reported findings and improves our understanding of observed phenomena by removing researcher bias, strengthening existing evidence and questioning past conclusions. Replication is an essential component of the self-correcting nature of science but, for too long the scientific community has overlooked the benefits of replication due to its perceived lack of novelty. However, a shift in attitudes has been making its way through various scientific disciplines, with finance now having its turn. In this study we survey the authors of Pacific-Basin Finance Journal replication studies to explore their motivations, experiences and seek their feedback on the specific process utilized by the journal to undertake the important task of facilitating the publication of replications.JEL classification: G00.

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders

PurposeTo identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). MethodsWe coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single-nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. ResultsAnalyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43 of 467 probands (9.2%), and prioritized variants of uncertain significance in 70 of 467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (eg, MYH10, KIF21B, TGFBR2, and TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (eg, CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (eg, TUBA4A, KIF5C, CTNNA1, KLB, and FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. ConclusionThis study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Identifying early language predictors: A replication of Gasparini et al. (2023) confirming applicability in a general population cohort

AbstractBackgroundIdentifying language disorders earlier can help children receive the support needed to improve developmental outcomes and quality of life. Despite the prevalence and impacts of persistent language disorder, there are surprisingly no robust predictor tools available. This makes it difficult for researchers to recruit young children into early intervention trials, which in turn impedes advances in providing effective early interventions to children who need it.AimsTo validate externally a predictor set of six variables previously identified to be predictive of language at 11 years of age, using data from the Longitudinal Study of Australian Children (LSAC) birth cohort. Also, to examine whether additional LSAC variables arose as predictive of language outcome.Methods & ProceduresA total of 5107 children were recruited to LSAC with developmental measures collected from 0 to 3 years. At 11–12 years, children completed the Clinical Evaluation of Language Fundamentals, 4th Edition, Recalling Sentences subtest. We used SuperLearner to estimate the accuracy of six previously identified parent‐reported variables from ages 2–3 years in predicting low language (sentence recall score ≥ 1.5 SD below the mean) at 11–12 years. Random forests were used to identify any additional variables predictive of language outcome.Outcomes & ResultsComplete data were available for 523 participants (52.20% girls), 27 (5.16%) of whom had a low language score. The six predictors yielded fair accuracy: 78% sensitivity (95% confidence interval (CI) = [58, 91]) and 71% specificity (95% CI = [67, 75]). These predictors relate to sentence complexity, vocabulary and behaviour. The random forests analysis identified similar predictors.Conclusions & ImplicationsWe identified an ultra‐short set of variables that predicts 11–12‐year language outcome with ‘fair’ accuracy. In one of few replication studies of this scale in the field, these methods have now been conducted across two population‐based cohorts, with consistent results. An imminent practical implication of these findings is using these predictors to aid recruitment into early language intervention studies. Future research can continue to refine the accuracy of early predictors to work towards earlier identification in a clinical context.WHAT THIS PAPER ADDSWhat is already known on the subject There are no robust predictor sets of child language disorder despite its prevalence and far‐reaching impacts. A previous study identified six variables collected at age 2–3 years that predicted 11–12‐year language with 75% sensitivity and 81% specificity, which warranted replication in a separate cohort.What this study adds to the existing knowledge We used machine learning methods to identify a set of six questions asked at age 2–3 years with ≥ 71% sensitivity and specificity for predicting low language outcome at 11–12 years, now showing consistent results across two large‐scale population‐based cohort studies.What are the potential or clinical implications of this work? This predictor set is more accurate than existing feasible methods and can be translated into a low‐resource and time‐efficient recruitment tool for early language intervention studies, leading to improved clinical service provision for young children likely to have persisting language difficulties.